The first reversible radioligand for the hVMAT2 [3H]reserpine binding site

描述(申请人提供)：滥用甲基苯丙胺(MA)是一个主要的健康问题。大约有1000万美国人至少使用过MA一次。长期使用MA具有深远的健康后果，并具有巨大的社会影响。国家药物滥用研究所对发现解决这一问题的药物表示了极大的兴趣。然而，目前还没有治疗MA成瘾的药物。MA是位于单胺能神经末梢细胞内储存小泡上的囊泡型单胺转运体2(VMAT2)的底物。这个第一阶段项目的目标是设计一种有效的和选择性的放射性配体，在与VMAT2的功能活性偶联的结合部位可逆地标记VMAT2。一种与VMAT2功能活性相关的可逆[~3H]配体将加速研究，以发现治疗MA滥用的药物。这里提出的独特的配体旨在通过抑制VMAT2上很少探索的[~3H]利血平结合位点来抑制VMAT2的摄取。我们的实验室已经证明，一种新型芳基哌啶基喹唑啉(APQ)的先导化合物可以可逆地结合在VMAT2上的[~3H]利血平结合部位。这种化合物的优化现在将通过顺序的分子修饰来实现，包括VMAT2的结合效力和拮抗剂的效力，通过VMAT2对5-羟色胺和多巴胺摄取的抑制来衡量。将进行进一步的分子修饰，以优化对竞争结合位点的选择性。将引入拓扑变化来探索VMAT2抑制的三维要求。VMAT2结合部位的生物对映体选择性将通过评估对映体化合物来开发。化合物将进行修饰，以优化电子、空间和亲脂因子在VMAT2上的功能和抑制效力。该项目预计将对寻找MA药物疗法以及了解MA与以VMAT2为靶点的潜在药物的分子相互作用产生重大影响。 与公共卫生相关：滥用甲基苯丙胺，目前没有药物可用，具有深远的健康后果和重大的社会影响。该项目的目标是将放射性配体设计为分子工具，以探索 甲基苯丙胺及其生物靶标--囊泡单胺转运体。这些工具将加速寻找治疗甲基苯丙胺成瘾的药物。

DESCRIPTION (provided by applicant): Abuse of methamphetamine (MA) is a major health problem. About 10 million Americans have used MA at least once. Chronic MA use has far reaching health consequences and has a tremendous societal impact. The National Institute on Drug Abuse has expressed considerable interest in the discovery of medications to address this problem. However, currently no medications are available for treatment of MA addiction. MA is a substrate for the Vesicular Monoamine Transporter-2 (VMAT2) located on intracellular storage vesicles in monoaminergic nerve terminals. The goal of this Phase 1 project is to design a potent and selective radioligand that reversibly labels the VMAT2 at a binding site that is coupled to functional activity of the VMAT2. A reversible [3H]ligand linked to functional activity f the VMAT2 will accelerate research toward discovery of medications for MA abuse. The unique ligands proposed here are designed to inhibit VMAT2 uptake by inhibition of the little explored [3H]reserpine binding site on VMAT2. A lead compound in the novel class of arylpiperidinylquinazolines (APQ) has already been demonstrated in our laboratories to bind reversibly at the [3H]reserpine binding site on the VMAT2. Optimization of this compound will now be achieved by sequential molecular modification with respect to binding potency at the VMAT2 and antagonist potency, as measured by inhibition of serotonin and dopamine uptake by the VMAT2. Further molecular modification will be conducted to optimize selectivity against competing binding sites. Topological changes will be introduced to explore the three-dimensional requirements of VMAT2 inhibition. Bioenantioselectivity of the VMAT2 binding site will be exploited by evaluation of enantiopure compounds. Compounds will be modified to optimize electronic, steric and lipophilic factors on functional and inhibitory potency at VMAT2. This project is expected to have a high impact on the search for MA pharmacotherapies as well as on the understanding of the molecular interaction of MA and potential medications that target the VMAT2. PUBLIC HEALTH RELEVANCE: Methamphetamine abuse, for which there are currently no medications available, has far reaching health consequences and a substantial societal impact. The goal of this project is to design radioligands as molecular tools to explore the interaction of methamphetamine with its biological target, the Vesicular Monoamine Transporter. These tools will accelerate the search for medications for methamphetamine addiction.